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Aberrant polymorphonuclear neutrophil (PMN) accumulation in tissues induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and \"do not eat me\" signals due to impaired synthesis of the deubiquitinase A20. Decreased A20 levels, in turn, activated the transcription factor NF-κB and the secretion of MIP2α (human homolog of IL-8) in ECs. EC-secreted MIP2α/IL-8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in ECs or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg-/- mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC/Erg/A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.

Aberrant neutrophil (PMN) accumulation in the tissue induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and 'do not eat me' signals due to impaired synthesis of the deubiquitinase, A20. Decreased A20 levels, in turn, activated the transcription factor NFκB and the secretion of MIP2α (human homolog of IL8) in ECs. EC-secreted MIP2α/IL8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in EC or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg-/- mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC-Erg-A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN-CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.Aberrant neutrophil (PMN) accumulation in the tissue induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and 'do not eat me' signals due to impaired synthesis of the deubiquitinase, A20. Decreased A20 levels, in turn, activated the transcription factor NFκB and the secretion of MIP2α (human homolog of IL8) in ECs. EC-secreted MIP2α/IL8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in EC or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg-/- mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC-Erg-A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN-CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.

Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/-mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK- deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.